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Targeting the Tumor Microenvironment in Cancer: Why Hyaluronidase Deserves a Second Look

Clifford J. Whatcott, Haiyong Han, Richard G. Posner, Galen Hostetter and Daniel D. Von Hoff
Clifford J. Whatcott
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Haiyong Han
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Richard G. Posner
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Galen Hostetter
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Daniel D. Von Hoff
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DOI: 10.1158/2159-8290.CD-11-0136 Published September 2011
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    Figure 1.

    Invading epithelial tumor cells and the associated tumor microenvironment. Dissolution of the basement membrane is accompanied by the production and secretion of numerous ECM components, including the collagens, fibronectin, laminin, and HA, as part of the myofibroblast-mediated desmoplastic reaction. Infiltrating immune cells also contribute to the signaling involved in the desmoplastic reaction. Expansion of the stromal compartment and production of the ECM proteins are thought to result in greater intratumoral pressure and contribute to a reduction in effective drug delivery. Inset, chemical structure of HA. HA is a linear polysaccharide composed of repeating units of glucuronic acid and N-acetylglucosamine. HA is a nonsulfated GAG and participates as an integral component of the ECM.

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  • ECM componentFunctional role in chemoresistance
    Collagen I, III, IVEnhances tumor cell proliferation, structural support of ECM
    DecorinBinds TGF-β, tightens collagen fibrils
    HASynergizes with collagen network, increases interstitial fluid pressure
    VersicanEnhances tumor cell proliferation, confers resistance to apoptosis
    FibronectinConfers resistance to apoptosis
    LamininConfers resistance to apoptosis
    Osteonectin/SPARCEnhances tumor cell proliferation and metastasis
  • Table 1.

    Early clinical studies investigating the coadministration of bovine hyaluronidase with chemotherapy

    StudyTrial typeTumor typeChemotherapyNumber of patientsEndpointResults
    Klocker et al. (16)Phase IIAdv. SCC-HNCisplatin/vindesine48ResponseCR in 84%, 47% survival >5 y
    Baumgartner et al. (12)Phase IIIBladder cancerMitomycin C56Recurrence27% vs. 59% recurrence in HYAL-treated vs. untreated
    Pillwein et al. (14)Phase IIMalignant brainCarboplatin/etoposide40Survival3-y survival, 84% vs. 50% in HYAL-treated vs. untreated
    Smith et al. (13)Phase IKaposi's sarcomaVinblastine6Toxicity/recurrence0% vs. 50% recurrence in HYAL-treated lesions, no added toxicity
    Baumgartner et al. (20)Phase IGastrointestinal and othersAdriamycin and others12Toxicity/recurrencePR/MR in 5 of 12 resistant, no added toxicity
    • Abbreviations: Adv. SCC-HN, advanced squamous cell carcinoma of the head and neck; CR, complete response; HYAL, hyaluronidase; MR, minimal response; PR, partial response

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Cancer Discovery: 1 (4)
September 2011
Volume 1, Issue 4
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Targeting the Tumor Microenvironment in Cancer: Why Hyaluronidase Deserves a Second Look
Clifford J. Whatcott, Haiyong Han, Richard G. Posner, Galen Hostetter and Daniel D. Von Hoff
Cancer Discov September 1 2011 (1) (4) 291-296; DOI: 10.1158/2159-8290.CD-11-0136

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Targeting the Tumor Microenvironment in Cancer: Why Hyaluronidase Deserves a Second Look
Clifford J. Whatcott, Haiyong Han, Richard G. Posner, Galen Hostetter and Daniel D. Von Hoff
Cancer Discov September 1 2011 (1) (4) 291-296; DOI: 10.1158/2159-8290.CD-11-0136
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    • Abstract
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    • Hyaluronan and Its Role in Cancer
    • Targeting Hyaluronan
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